Chaves et al.

Journal of Neuroinflammation 2010, 7:6 JOURNAL OF

http://www.jneuroinflammation.com/content/7/1/6
NEUROINFLAMMATION

RESEARCH Open Access

Serum levels of S100B and NSE proteins in

Alzheimer’s disease patients
Márcia L Chaves1*, Ana L Camozzato1, Eduardo D Ferreira1, Isabel Piazenski1, Renata Kochhann1, Oscar Dall’Igna2,
Guilherme S Mazzini2, Diogo O Souza2, Luis V Portela2

Abstract
Background: Alzheimer’s disease is the most common dementia in the elderly, and the potential of peripheral
biochemical markers as complementary tools in the neuropsychiatric evaluation of these patients has claimed
further attention.
Methods: We evaluated serum levels of S100B and neuron-specific enolase (NSE) in 54 mild, moderate and severe
Alzheimer’s disease (AD) patients and in 66 community-dwelling elderly. AD patients met the probable NINCDS-
ADRDA criteria. Severity of dementia was ascertained by the Clinical Dementia Rating (CDR) scale, cognitive
function by the Mini Mental State Examination (MMSE), and neuroimage findings with magnetic resonance
imaging. Serum was obtained from all individuals and frozen at -70°C until analysis.
Results: By comparing both groups, serum S100B levels were lower in AD group, while serum NSE levels were the
same both groups. In AD patients, S100B levels were positively correlated with CDR scores (rho = 0.269; p = 0.049)
and negatively correlated with MMSE scores (rho = -0.33; P = 0.048). NSE levels decreased in AD patients with
higher levels of brain atrophy.
Conclusions: The findings suggest that serum levels of S100B may be a marker for brain functional condition and
serum NSE levels may be a marker for morphological status in AD.

Background permanent stimulus for finding peripheral markers of

Alzheimer’s disease (AD) is a progressive brain disorder central nervous system (CNS) alterations. In this con-
that results in memory impairment, personality altera- text, a number of proteins have been proposed as per-
tions, global cognitive dysfunction, and functional ipheral biochemical markers of neuronal damage and
impairments [1]. It is the most common dementia in glial injury/activation, which peripheral assessment may
the elderly, accounting for 60-80% of cases, and it is represent a relevant step forward in the diagnostic and
estimated to affect more than 4 million of USA citizens monitoring of CNS diseases [5-9]. For this reason, the
[2]. The lifespan of individuals diagnosed with AD is clinical usefulness of peripheral biochemical markers as
reduced by about 50% as compared with those of similar complementary tool in the neuropsychiatric evaluation
age without disease, and the survival expectancy is nega- has claimed further attention.
tively associated with the severity of the disease at the S100B and neuron specific enolase (NSE) are brain
time of diagnosis [3]. Furthermore, there is no definitive derived proteins extensively studied as peripheral bio-
ante-mortem diagnostic test for AD, and when the clini- chemical markers for brain injury [8-11]. S100B is a cal-
cal diagnosis is made, is difficult to access and following cium binding protein physiologically produced and
the course of neural cells loss [4]. released predominantly by astrocytes, whereas NSE is a
The inherent hurdles of studying brain tissues in cytoplasmatic glycolytic pathway enzyme, being the gg
human populations, especially in vivo, are the isoform mainly neuronal [12,13]. Since their levels may
increase in CSF and/or blood in several brain patholo-
gies, both proteins are considered to be markers of
* Correspondence: mchaves@hcpa.ufrgs.br
1
Serviço de Neurologia, Hospital de Clínicas de Porto Alegre, Rua Ramiro
astrocytic damage/reaction (S100B) and neuronal
Barcelos 2350, 90035-003 Porto Alegre, RS, Brazil damage (NSE) [14-16]. Considering the prominent
© 2010 Chaves et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
Chaves et al. Journal of Neuroinflammation 2010, 7:6
http://www.jneuroinflammation.com/content/7/1/6
neural death observed in the course of AD, some studies
have also attempted to clinically evaluate the levels of
these proteins, resulting in contradictory findings
[17-21], but alternatively, experimental and human stu-
dies have strengthened the belief that S100B is impli-
cated in the mechanisms underlying neurodegeneration
in AD [22-24]. Accordingly, it was reported an associa-
tion between the deposition of cerebral amyloid beta
protein and the presence of activated astrocytes over
expressing S100B.
Furthermore, life-long over expression of S100B in
Down syndrome patients and transgenic mice cause
neuronal and glial morphological alterations similar to
those found in AD patients, as well as behavioral deficits
in animals [17-19]. These conjectures have been the
rational for studying CSF/serum S100B and NSE levels
in AD as markers of neurodegeneration and severity of
the disease. Also, it is important to take into account
that, due to the insufficiency of professional, methodolo-
gical and background conditions, the diagnosis of AD in
non specialized centers may not be accurately per-
formed, which encourage identifying potential peripheral
biomarkers for AD, aiming an easier, accurate and wide-
spread diagnosis [4].
The major aim of our study was to evaluate serum
S100B and NSE levels (more readily assessed than CSF)
in AD patients and control elderly individuals without
pathological cognitive impairment. In addition, we
searched for correlations among their levels and the
severity of dementia, cognitive status and brain morpho-
logical changes accessed by MRI.
Methods
Participants and study design
A cross-sectional study with AD patients and control
community-dwelling elderly was carried out. Thirty six
AD patients met the probable NINCDS ADRDA criteria
[25] and were recruited from the Neurogeriatric outpati-
ent clinic of Hospital de Clínicas de Porto Alegre
(HCPA), Porto Alegre, RS, Brazil. Severity of dementia
was assigned with the Clinical Dementia Rating (CDR)
scale and the cognitive status was assessed by Mini
Mental State Examination (MMSE) [26-28]. The CDR is
a scale in which CDR = 0 denotes no cognitive impair-
ment, and the remaining points indicate various stages
of dementia: CDR = 1 - mild dementia, CDR = 2 - mod-
erate dementia, and CDR = 3 - severe dementia. Exclu-
sion criterion for patients was the presence of any other
neurological or psychiatric condition (except if asso-
ciated with AD), or diseases that could lead to confusion
in the diagnosis of AD.
A control group composed of 66 community-dwelling
elderly individuals was recruited from the catchment’s
area of the same hospital. The inclusion criteria were
Page 2 of 7
age higher than 60 years and a CDR = 0. Controls were
excluded if they presented chronic renal disease, history
of significant head injury or stroke; other psychiatric
conditions such as major affective disorder or evidence
of current depression; uncorrectable vision or hearing
loss or other conditions such as substance abuse or use
of medications that could impair cognitive function.
AD patients were evaluated with brain magnetic reso-
nance imaging. Patients were additionally submitted to a
complete medical and laboratory evaluation. Educational
attainment was checked for all participants.
Blood samples (3 ml) for S100B and NSE levels mea-
surement were collected by venipuncture with a tube
(vacuum system) without anticoagulants by a trained
professional. Serum (was obtained by centrifugation at
5,000 × g for 5 min and, soon thereafter, it was frozen
at -70°C until analysis.
Brain MRI
Neuroimaging data were acquired with MRI equipments
of 1.5 T (Siemens Magneton Vision Plus or Siemens
Symphony, Siemens Medical Systems, Erlang, Germany)
with the axial SE and TSE pulse sequences, in T2, (TR:
7,100; TE: 115; slice width: 5 mm; FOV: 230; matrix:
345 × 512), FLAIR (TR: 9,000; TE: 110; slice width: 5
mm; FOV: 230; matrix: 154 × 256) and IR (TR: 1,450,
TE: 115, slice width: 3 mm, FOV: 200; matrix: 160 ×
256). Sagital SE images were also acquired in T1 (TR:
580; TE: 14; slice width: 5 mm; FOV: 260; matrix: 156 ×
256). The average duration of the exam was 30 minutes.
Degree of brain atrophy was measured according to
the method of Meese et al. 1980 [29]. Two transversal
lines were established in the axial plane of the brain, on
TSE pulse sequence, in T2. The first estimated the
latero-lateral diameter of the lateral ventricles (D1), and
the second, between the parietal bones. The brain atro-
phy index (BAI) was calculated by the equation BAI =
10 - (D2/D1).
Three degrees of brain atrophy were also established:
mild (level 1), moderate (level 2), and severe (level 3),
based on the 25, 50 and 75 percentile values of the
groups combined.
Serum S100B and NSE analyses
A quantitative monoclonal two-site immunoluminometric
assay LIA-mat Sangtec 100 (BYK-Sangtec, Germany), was
used for measuring S100B levels in 100 (L of samples. The
immunoluminometric assay is composed of three mono-
clonal antibodies specific to subunit b of S100 and a tracer
antibody, which is bound to isoluminol. Oxidation of iso-
luminol is started by injection of an alkaline peroxide solu-
tion and catalyst solution. The immunological reaction is
detected by light reaction [30]. The determinations were
carried out in two different experiments. The S100B
Chaves et al. Journal of Neuroinflammation 2010, 7:6 Page 3 of 7
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calibration curve was linear up to 20 (μg/L, and the CVs Table 1 Demographic, clinical and biochemical data of
for duplicates across the entire concentration range for the subjects.
calibrators and samples were < 5%. The detection limit of Control group AD patients P value
the assay is 0.02 (μg/L, as provided by the supplier of the (N = 66) (N = 54)
LIA-mat Sangtec100 assay. Internal controls provided by Age (years) (mean ± SD) 76.56 ± 5.46 77.13 ± 7.57 0.773
manufacturer was used to determine inter- assay variation, Gender
which was also <5%. S100B levels are expressed as mean ± Male (%) 20 (30%) 18 (33%) 0.681
standard deviation. Female (%) 46 (70%) 36 (67%)
NSE level was evaluated in serum samples by an elec- Education (in years) 8.48 ± 5.24 5.23 ± 4.38 0.01
trochemiluminescence assay kit (ECLIA, Roche Diagnos- MMSE (mean ± SD) 27.09 ± 2.99 10.98 ± 6.44 0.001
tics, USA). This is a quantitative method that uses a CDR (%)
monoclonal antibody specific for NSE and labeled with 0 66 (100%) - 0.001
a ruthenium complex, which produces light emission 1 (mild) - 12 (22%)
when excited [6]. Reactions and quantification were per- 2 (moderate) - 22 (41%)
formed in duplicate by a fully automatized equipment 3 (severe) - 20 (37%)
Elecsys-2010 (Roche Diagnostics Corporation®). Internal S100B (μg/l) (mean ± SD) 0.21 ± 0.36 0.08 ± 0.06 0.008
software and controls provided by the manufacturer NSE (μg/l) (mean ± SD) 9.54 ± 5.28 9.28 ± 3.86 0.832
allow controlling the quality of assay. The NSE calibra- MMSE: Mini Mental State Examination. CDR: Clinical Dementia Rating
tion curve was linear up to 370 (μg/L), and the CVs for
duplicates across the entire concentration range for the There was a statistically significant difference in serum
calibrators, controls and samples were < 5%. The detec- S100B levels between AD and control group (0.08 ±
tion limit was 0.015 μg/L. Serum NSE level is expressed 0.06 vs. 0.21 ± 0.36, μg/L, respectively; p = 0.008), while
as μg/L (mean ± S.D.). the serum NSE levels were similar in both groups (9.28
± 3.86 vs. 9.54 ± 5.28, μg/L, respectively; p = 0.832).
Ethical aspects Serum S100B and NSE levels did not vary with age
The study was conducted in accordance with the Declara- (data not shown).
tion of Helsinki, and was approved by the Ethics Commit-
tee for Medical Research of the university hospital where Serum S100B and NSE levels in AD patients
it was developed. Informed consent was obtained from the A positive significant correlation among CDR scores and
subjects, their nearest relatives, or both. S100B levels was observed among AD patients (rho =
0.269; p = 0.049, data not shown). Additionally, among
Statistical analysis AD patients, there was a statistically significant differ-
Descriptive statistics are presented with mean ± stan- ence in serum S100B levels between mild and severe
dard deviation for parametric variables, and absolute CDR scores (0.050 ± 0.013 vs. 0.091 ± 0.022, respec-
and percentage frequency for categories. Comparison of tively; p = 0.022) (Figure 1). No differences in serum
S100B and NSE serum levels between groups was made NSE level were observed among CDR categories of AD
using one-way ANOVA with Tukey test, and Student’s t patients (data not shown).
test for independent samples. Correlation between There was a significant negative correlation between
S100B and MMSE was performed with Spearman’s coef- serum S100B levels and cognitive performance -
ficient. Chi-square test with Yates or Fisher exact cor- expressed as a positive correlation between S100B levels
rection was used for the analysis of association of CDR and MMSE score (Spearman correlation rho = - 0.35; p
and MRI findings categories. Comparison ANOVA fol- = 0.01; Figure 2). A negative correlation between serum
lowed by Tukey test and Student t test were used to NSE levels and MMSE was also observed (Spearman
analyze differences between serum levels of S100B (AD correlation rho = - 0.48; p = 0.017, data not shown).
and controls) and CDR groups. A p value < 0.05 was
considered statistically significant. Statistical analyses MRI and S100 and NSE serum levels in AD patients
were carried out with the SPSS 16.0 for Windows. Table 2 shows the correlation among serum NSE and
S100B levels with the degree of brain atrophy accessed
Results by MRI in AD patients. NSE levels significantly
Comparisons between AD and Control group decreased with the brain atrophy severity. Serum S100B
The demographic, clinical and biochemical characteris- levels were not affected by brain atrophy. Despite litera-
tics of AD patients and control elderly group are ture suggest the opposite [31]; there was no correlation
depicted in Table 1. The MMSE and CDR scales were among severity of dementia (evaluated by CDR scale)
altered in AD patients compared to control group. and the MRI findings (Table 3).
Chaves et al. Journal of Neuroinflammation 2010, 7:6 Page 4 of 7
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Table 2 Serum S100B and NSE levels (mean ± SD)

according to brain MRI findings in AD patients.
Degree of brain atrophy
Percentil 25 Percentil 50 Percentil 75
(N = 16) (N = 26) (N = 12)
S100B 0.09 ± 0.05 0.07 ± 0.06 0.07 ± 0.06
a,b a,c b,c
NSE 14.52 ± 4.08 7.98 ± 1.52 6.64 ± 1.17
a ≠ a: p < 0.001
b ≠ b: p = 0.001
c ≠ c: p = 0.077

there were a positive correlation between S100B levels

Figure 1 Serum S100B level (mean ± SD) according to severity
of dementia in AD (CDR scale; 1 mild, 2 moderate; 3 severe) -
One-way ANOVA (F = 3.685).
Discussion
The main goal of this work was to investigate the course
of brain neurodegenerative processes in AD patients
through biochemical brain markers, neuropsychological
and neuroimaging evaluations. Our main findings were:
i) although serum NSE levels were not different between
AD patients and control elderly individuals, serum of
S100B levels were significantly lower in DA patients; ii)
and AD severity (evaluated by CDR and MMSE) as well
as a negative correlation between NSE levels and the
severity of morphological brain alterations, evaluated by
MRI.
In the last years the possibility of evaluating brain
damage/activity through quantification of neuronal and
glial derived proteins (such as S100B and NSE) in per-
ipheral samples has gained appropriate attention in clin-
ical and experimental settings [5,14,20,32]. However,
S100B and NSE proteins are also expressed in other non
neural cell types under physiological and pathological
conditions. Thus, the brain specificity of these proteins
has been questionable by some works, including from
our laboratory [33], when assessing serum samples.
Moreover, recent epidemiological and clinico-pathologic
data suggest overlaps between AD and cerebrovascular
lesions that may magnify the effect of mild AD pathol-
ogy and promote progression of cognitive decline or
even may precede neuronal damage and dementia [34].
So, we cannot rule out that vascular lesions also could
account for increase S100B levels.
Despite the controversies on their brain specificity,
S100B and NSE have been investigated in different brain
diseases as peripheral markers of therapeutic interven-
tions, as well as of neurological and neuropsychological
outcome [14,16,22-24]. Additionally, a recent work sug-
gests that blood-brain barrier permeability may also be
damaged even at an early stage of AD indicating differ-
ent blood-brain-CSF compartmental kinetics [35]. Thus,
the leakage of proteins from brain to blood could be
facilitated.

Table 3 Distribution of dementia severity (CDR

categories) according to brain MRI findings in AD
patients.
CDR Degree of brain atrophy
Percentil 25 Percentil 50 Percentil 75
(N = 16) (N = 26) (N = 12)
Mild (N = 12) 3 (19%) 7 (27%) 2 (17%)
Figure 2 Correlation between S100B serum levels and Mini Moderate (N = 22) 7 (44%) 8 (31%) 7 (58%)
Mental State Examination (MMSE) score: AD patients - Severe (N = 20) 6 (37.5%) 11 (42%) 3 (25%)
Spearman rho = - 0.35; P = 0.01.
Chi-square Fisher Exact = 2.67; p = 0.632
Chaves et al. Journal of Neuroinflammation 2010, 7:6
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There is a considerable number of clinical studies
regarding CSF levels of S100B in AD, which from the per-
spective of cerebral protein release provides more sensitiv-
ity and specificity than serum samples, however, the
availability of CSF samples is somewhat limited for routine
clinical use [20,21,36]. These previous studies showed dis-
crepant results with respect to the differences in S100B
levels between AD and control groups and also to clinical
associations. While some studies have reported increased
CSF levels of S100B in AD patients compared to controls
[21,36], others did not find any difference [20]. There are
also reports suggesting a positive correlation between CSF
S100B levels and MMSE, and a negative correlation with
severity of dementia by CDR scale [20] while in others
CSF S100B levels did not correlate with impaired cognitive
status evaluated by MMSE [21,36].
In contrast to these cited works, here we demon-
strated AD patients a positive correlation between
serum S100B levels and brain function (evaluated by
MMSE and CDR). Ethnic differences, education, prior
life style and the predominance of female in our study,
compared to others, could account for the differences
observed among the previous published results. Consid-
ering that in our work MMSE and CDR scales identified
patients with impaired cerebral functionality affected by
AD and that the S100B levels were higher in more
severely affected patients, we preliminarily suggest that
serum S100B levels could help to distinguish severity or
to follow up the progression of dementia in AD disease,
even though the diagnosis is based on clinical investiga-
tions. This result may reflect the participation of this
protein in the pathogenesis of AD. Indeed, glial cells
particularly microglia and astrocytes are able to modu-
late cerebral plasticity and to protect brain from insults
[13]; thus, in this context the increase in S100B could
indicate astrocytic reaction to neuronal injury (reactive
astrogliosis) in AD patients. Once activated, these cells
increase the expression of substances that can partici-
pate in the excitotoxicity and inflammatory processes
that occur during the evolution of AD [37].
Further, dysfunction of glial cells may promote neu-
rodegeneration and, eventually, the retraction of neu-
ronal synapses, which leads to cognitive deficits [38].
However, our major concern is regarding the decreas-
ing levels of S100B in total AD group compared to
controls. This finding was confirmed by an additional
experiment with a new set of patients. Interestingly,
the severity of CDR score was associated with eleva-
tions in serum S100B levels, contrasting to our pre-
vious findings with schizophrenic patients [39], when
the levels were more elevated in the early onset of dis-
ease. In this context, increased astrocytic expression of
S100B could be involved in the progression of brain
neuropathological changes and behavioral deficits
Page 5 of 7
observed in patients and animal models [20,13,40-42].
While in this study S100B levels in AD patients did
not correlate with brain morphological changes evalu-
ated by MRI, lower serum levels of NSE were related
to higher degree of atrophy and brain macroscopic
alterations. Furthermore, this loss was not associated
with dementia severity in AD patients. The lack of a
correlation with atrophy and cognition reported here is
somewhat curious as many recent reports of the litera-
ture suggest the opposite [31].
Levels of NSE have been shown to be elevated in
acute phase of several disorders of the CNS [43-47].
This data could preliminary suggest that AD patients,
prior the onset of symptoms, could have altered NSE
levels, which is now reflected by brain atrophy and ven-
tricle enlargement. However, the reports of CSF NSE
vary from decreased levels [17], no difference [19] to
increased levels [48]. Interestingly, Palumbo et al. 2008
[48] showed that CSF NSE level has the same behavior
as the other accepted markers of AD, being correlated
with Abeta42 and total protein tau (h-tau).
Taking into consideration, the strong association of
the prognosis of AD patients with the severity of
dementia at the diagnosis [3], and the difficulty of evalu-
ating the degree of neural cells loss in AD [4], further
experimental and clinical studies regarding these serum
markers in AD disease should be encouraged.
Conclusions
In conclusion, we showed that in AD patients the serum
S100B levels increased with the severity of the disease
whereas decreased serum levels of NSE were associated
with increased brain morphological damage.
Acknowledgements
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES),
Fundação de Amparo à Pesquisa do Rio Grande do Sul (FAPERGS) and
Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq),
IBN.Net/Finep, INCT for Excitotoxicity and Neuroprotection/CNPq.
Author details
1
Serviço de Neurologia, Hospital de Clínicas de Porto Alegre, Rua Ramiro
Barcelos 2350, 90035-003 Porto Alegre, RS, Brazil. 2Programa de Pós-
graduação em Bioquímica, PPG-Bioq. Departamento de Bioquímica, ICBS,
UFRGS, Ramiro Barcelos 2600, anexo, 90035-003 Porto Alegre, RS, Brazil.
Authors’ contributions
MLC designed the study, was responsible for the statistical design of the
study, supervised the data collection, and wrote the manuscript. ALC was
responsible for carrying out the statistical analysis and helped with
reviewing the manuscript. EDF supervised the data collection, was
responsible for carrying out the statistical analysis and wrote the manuscript.
IP, RK, OD and GSM collected the data and assisted with writing the
manuscript. DOS and LVP designed the study, made the biochemical
measurements and reviewed the manuscript. All authors read and approved
the final manuscript.
Competing interests
The authors declare that they have no competing interests.
Chaves et al. Journal of Neuroinflammation 2010, 7:6
http://www.jneuroinflammation.com/content/7/1/6
Received: 4 May 2009
Accepted: 27 January 2010 Published: 27 January 2010
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doi:10.1186/1742-2094-7-6
Cite this article as: Chaves et al.: Serum levels of S100B and NSE
proteins in Alzheimer’s disease patients. Journal of Neuroinflammation
2010 7:6.

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